Targeted Gene Transfer of Hepatocyte Growth Factor to Alveolar Type II Epithelial Cells Reduces Lung Fibrosis in Rats

Proliferation of type II cells is required for maintenance of the alveolar epithelium and for restoration after lung injury. Although various known growth factors have been reported to stimulate type II cell proliferation in vitro, there is very little knowledge on which growth factors are present in the lung in vivo. We have previously reported that rat lavage fluid contains a mitogen(s) for type II cells, and this study was de signed to identify the growth factor(s) in this biological fluid for type II cells. The mitogenic activity was purified by sequential chromatography on blue Sepharose and heparin Sepharose. Hepatocyte growth factor (HGF) and acidic fibroblast growth factor by Western analysis. The amount of HGF recovered by lavage was approximately 6 ng/rat. By a use of neutralizing antibodies for different growth factors, HGF was found to be responsible for most of the stimulatory activity for rat type II cells in the partially purified lavage fluid. In addition to HGF, rat lavage fluid also contained potent mitogenic activity for fibroblasts. Finally, we have demonstrated that much of the mitogenic activity in salt extracts of human lung is HGF. We conclude that HGF is found in rat lavage fluid and is possibly an important mitogen for adult type II cells in vivo.

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Analysis of Progestin Effects on Hepatocyte Growth Factor Signaling Pathways in Relation to Proliferation and Alveolar Morphogenesis of Normal Mammary Epithelial Cells in Vitro

10.21236/ada416749 ◽

2003 ◽

Author(s):

Kyle T. Smith

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Hepatocyte Growth Factor ◽

Signaling Pathways ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Growth Factor Signaling ◽

Hepatocyte Growth ◽

Normal Mammary Epithelial

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Cbl-transforming Variants Trigger a Cascade of Molecular Alterations That Lead to Epithelial Mesenchymal Conversion

Molecular Biology of the Cell ◽

10.1091/mbc.11.10.3397 ◽

2000 ◽

Vol 11 (10) ◽

pp. 3397-3410 ◽

Cited By ~ 23

Author(s):

Tanya M. Fournier ◽

Louie Lamorte ◽

Christiane R. Maroun ◽

Mark Lupher ◽

Hamid Band ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Hepatocyte Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Morphological Changes ◽

Cell Spreading ◽

Mesenchymal Transition ◽

Amino Terminal ◽

Src Homology ◽

Hepatocyte Growth

Dispersal of epithelial cells is an important aspect of tumorigenesis, and invasion. Factors such as hepatocyte growth factor induce the breakdown of cell junctions and promote cell spreading and the dispersal of colonies of epithelial cells, providing a model system to investigate the biochemical signals that regulate these events. Multiple signaling proteins are phosphorylated in epithelial cells during hepatocyte growth factor–induced cell dispersal, including c-Cbl, a protooncogene docking protein with ubiquitin ligase activity. We have examined the role of c-Cbl and a transforming variant (70z-Cbl) in epithelial cell dispersal. We show that the expression of 70z-Cbl in Madin-Darby canine kidney epithelial cells resulted in the breakdown of cell–cell contacts and alterations in cell morphology characteristic of epithelial–mesenchymal transition. Structure–function studies revealed that the amino-terminal portion of c-Cbl, which corresponds to the Cbl phosphotyrosine-binding/Src homology domain 2 , is sufficient to promote the morphological changes in cell shape. Moreover, a point mutation at Gly-306 abrogates the ability of the Cbl Src homology domain 2 to induce these morphological changes. Our results identify a role for Cbl in the regulation of epithelial–mesenchymal transition, including loss of adherens junctions, cell spreading, and the initiation of cell dispersal.

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